Recent data suggests the possibility that antiarrhythmic agents may protect against protentially lethal arrhythmias independently of their suppressive effect on chronic premature ventricular contractions (PVC's), suggesting a dissociation between "antifibrilltory" and "antidysrhythmic" drug effects. Viewing the drugs as the intervention, and prevention of various forms of ventricular arrhythmias as the response of the risk factor, the proposed study is designed to evaluate the validity of various possible end-points of arrhythmia management. The project includes two categories of response variables: (1) forms of ventricular arrhythmias (e.g., PVC's, ventricular tachycardia [VT], ventricular fibrillation [VF]), and (2) clinical settings of ventricular arrhythmias (stable chronic heart hisease, acute myocardial infarction, survivors of prehospital cardiac arrest). There will also be two categories of intervention variables: (1) variations in free versus total drug concentration, and (2) the role of active metabolites. By measuring and correlating intervention and response subsets, we plan to test the hypotheses that (1) the relationship between an antiarrhythmic intervention and acute or chronic PVC's, (2) that effectiveness, measured in relation to plasma concentrations required to prevent ventricular arrhythmias, varies as a function of clinical settings; and (3) that the relationship between the intervention and the response vary with fluctuatons in free drug concentrations which are consequences of changes in binding of antiarrhythmic agents to circulating compounds. We plan first to measure the concentration-response relationships between total plasma levels of antiarrhythmic agents and PVC suppression in chronic and acute heart disease, and in patients who have have both recurrent VT and chronic PVC's. After validating techniques for measuring free-drug concentrations for 3 agents having different steady-state binding characteristics, we will study concentration-response relationships for free drug concentrations in various response subsets. The ultimate goal of these studies is to provide better guiding principles for the use of antiarrhythmic agents in protection against potentially lethal arrhythmias.